Modulation of phagocyte activation by the synthetic chemoattractant fmet-leu-phe has been studied using membrane potential and calcium sensitive fluorescent probes, and assays of superoxide generation and degranulation in PMN. Our data indicate modulation of fmet-leu-phe receptor affinity may be an important mechanism by which PMN adapt and respond to a gradient of chemoattractant during the process of chemotaxis. Related studies of neutrophil heterogeneity, which we described previously, revealed heterogeneity of fmet-leu-phe binding. All cells bind fmet-leu-phe to their plasma membrane in a nondisplaceable manner, in addition to internalizing the ligand. The subpopulation of PMN which depolarizes bound more peptide, and only these cells exhibit displaceable binding of fmet-leu-phe. Nondepolarizing cells could be induced to respond and display displaceable binding by pretreatment with cytochalasin B. Thus, functional heterogeneity exists among PMN and studies are underway to further define the significance of this finding. In other studies the effect of amphotericin B was determined. At concentrations achieved in vivo this drug causes PMN to depolarize and secrete their granule contents, produce superoxide anion, hydrogen peroxide and to aggregate. Thus, amphotericin B is a secretagogue for PMN and this may contribute to its toxic effects in vivo. The effect of histamine on PMN function has also been investigated. It was found that histamine reversibly and specifically inhibited oxidative metabolism, chemotaxis and membrane potential changes stimulated by fmet-leu-phe, but was without effect on functions stimulated by other agents such as phorbol myristate acetate. The histamine receptor which mediated these effects demonstrated affinity for both H1 and H2 analogues and only H2 antagonists (cimetidine) were capable of reversing the inhibitory effects of histamine.